Greater understanding of the adverse health effects of tobacco consumption and associated nicotine intake has led to a marked increase in research on the nature of nicotine addiction and its treatment. Addiction to nicotine, as described in past U.S. Surgeon General's reports on smoking, is widespread, with over 50 million smokers in the United States alone. Addiction to nicotine is a major barrier to an individual's ability to successfully and permanently stop smoking.
As with other addictions, addiction to nicotine encompasses two key components. One component is a physiological addiction to nicotine itself. The physiological addiction is mediated through adaptive changes in specific brain nicotine receptors that lead to typical withdrawal symptoms upon abstaining from nicotine. A second component is a complex behavioral component. The behavior component is linked to learned internal cues associated with various positive or negative emotional feelings tied to tobacco smoking or abstinence.
The physiological addiction to nicotine is significant. The American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (third edition, revised) lists the officially recognized diagnostic criteria for nicotine withdrawal as the presence of at least four of the following signs: (1) craving for nicotine; (2) irritability, frustration, anger; (3) anxiety; (4) difficulty concentrating; (5) restlessness; (6) decreased heart rate; and (7) increased appetite or weight gain.
Differing approaches to smoking cessation attempt to address the physiological addition and the behavior component. The approaches range from stopping "cold turkey," hypnosis, electroshock, acupuncture, behavioral counseling, to various forms of therapeutic support. Nicotine replacement therapies such as chewing gum and transdermal patches, in conjunction with behavioral counselling, are now commonly used to treat nicotine withdrawal and as an aid to smoking cessation. However, long-term success through the use of nicotine replacement is low. In general, 25% or less of the individuals attempting to stop nicotine use are abstaining 12 months after treatment.
There is a great need for treatment systems which promote permanent smoking cessation. There also is a need for products that provide temporary relief of tobacco/nicotine withdrawal symptoms for individuals who use tobacco products, when such use is temporarily interrupted.
Individuals who use tobacco, and do not intend to stop such use, must often refrain from such use for extended periods of time. Airline personnel and passengers, hospital workers and patients, individuals working in chemical plants or with flammable materials and the like may need to temporarily curtail the use of tobacco products. The occurrence of nicotine withdrawal is also frequently associated with reduction in task performance efficiency. Prevention of nicotine withdrawal may alleviate or prevent such reductions in task performance.
Individuals who have stopped tobacco use and are past acute withdrawal symptoms often have acute nicotine cravings. A reduction in nicotine craving is useful for such individuals encountering situations that increase their urge to use tobacco. Such relief may increase the individual's ability to maintain abstinence from tobacco use.
Lobeline is the principal alkaloid obtained from the dried leaves and tops of Lobelia inflata, an annual plant of the Lobeliaceae family. Lobeline is a substituted piperidine compound that produces several physiological effects, some of which are similar to those produced by nicotine. It is believed that the pharmacological actions of lobeline are produced by its ability to bind to nicotine receptors in the brain and elsewhere in the body. Lobeline's potency in causing peripheral pharmacological effects, such as increases in blood pressure and heart rate, is significantly less than that of nicotine.
Lobeline has been proposed as a substitute for nicotine, to reduce dependence on nicotine and reduce the use of tobacco products. Although use of lobeline as a smoking cessation aid has been studied since at least the 1930's, its efficacy has been a matter of dispute.
Typical over-the-counter (OTC) products providing lobeline comprise Nicoban.TM., Bantron.TM., CigArrest.TM., NicFit.TM. and Smoker's Choice.TM.. All lobeline containing smoking cessation products sold in recent years have been non-prescription OTC products. The FDA reports that all OTC smoking cessation aids are ineffective and has taken the unusual step of declaring all such OTC products mislabeled in order to remove such products from the market. Most of the OTC products administered lobeline orally for absorption in the gastrointestinal tract. The directions with such products recommend a daily dose of up to 6 milligrams. Antacids are incorporated in some of the products to overcome gastrointestinal discomfort, a side-effect similar to that caused by nicotine. Higher oral doses may not be feasible because of the concomitant gastric upset.
Although there have been reports of using lobeline in oral formulations at doses in excess of 10 mg/day, nausea and even vomiting have been associated with such doses. A further problem with such oral dose regimens is that self-administration of as many as 18 tablets per day has been required. Patients may consider such a dosing regimen as intrusive, and such dosing regimen does not permit the physician to carefully control the administration of the drug or monitor patient compliance.
Lobeline is poorly absorbed from the gastrointestinal tract. Subjects desiring to substitute lobeline for nicotine are unable to take effective quantities of lobeline orally, due to adverse gastrointestinal effects. The oral products may not produce effective blood or tissue levels.
One product presently available, Smoker's Lozenges, contains lobeline in a candy lozenge. The lozenge is intended to dissolve slowly in the mouth to release lobeline. A second product, Smoker's Gum, contains lobeline in a gum base. The gum is intended to release lobeline slowly as the gum is chewed. The instructions with these products do not instruct users to retain the dissolved candy or gum fluids in the oral cavity. The normal reflex would urge users to swallow, severely limiting any buccal absorption of lobeline. Absorption of swallowed lobeline from the gastrointestinal tract may not avoid first pass metabolism by the liver.
These OTC products, as with other lobeline OTC products, have been subjected to FDA action questioning the efficacy of the formulation. It was believed that effective doses of lobeline could not be obtained without an invasive dosage form, such as injection.
The present invention is directed methods and articles of manufacture for delivering an effective amount of lobeline to the sublingual mucosa. The methods and articles of manufacture of the present invention provides relief from acute nicotine withdrawal, in a manner previously believed unattainable in a non-invasive dosage form. Such relief from acute nicotine withdrawal is directly applicable to individuals wanting to (1) temporarily abstain from smoking or otherwise using nicotine without suffering the full extent of nicotine withdrawal symptoms, or (2) cease using nicotine-containing products.